Duloxetine is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. It has been found to be useful in the treatment of stress urinary incontinence (SUI), depression, and pain management. The primary raw material in the synthesis of duloxetine is (S)-(+)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate (DNT-Oxal).
The preparation of DNT-Oxal is described in European Patent Application No. EP 457,559 A3 and International Patent Application Publication WO 2004/056,795 A, as well as in Deeter, J. et al, Tetrahedron Lett., 1990, 31, 7101. However, Deeter et al. fail to describe the procedure accurately, and do not disclose any crystalline form of DNT-Oxal.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, such as DNT-Oxal, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties, such as melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids, sharing the same molecular formula, yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly, so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
There is a need in the art for the discovery of new forms of DNT-Oxal and/or processes for their preparation.